EHA 2019 | Phase I first-in-human results of AMV564 in patients with relapsed/refractory acute myeloid leukemia (AML)

During the 24^th Meeting of the European Hematology Association (EHA) in Amsterdam, NL, Gail Roboz, Weill Cornell Medicine and The Weill Medical College of Cornell University, New York, US, presented an updated analysis from the first-in-human phase I trial of AMV564, a novel bispecific CD33/CD3 targeted immunotherapeutic, which was tested in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML).

Background

Professor (Prof.) Roboz highlighted that relapse is still very common and a prominent problem in AML, with patients who relapse generally succumbing to the disease within 1 year. She noted that chemotherapeutic agents, and hypomethylating agents, are equally unsuccessful with overall response rates (ORRs) ranging between 18% and 41% in selected studies. This, therefore, means that the AML field is looking for novel agents that can counteract the existing dismal outcome. One such area of novel agents gaining a lot of interest is immunotherapy.

AMV564 is a bivalent, bispecific CD33/CD3 T-cell engager;

• It has 2 binding sites for CD3 (expressed on T-cells) and 2 binding sites for CD33 (highly expressed in myeloid derived suppressor cells [MDSCs] and on >95% of AML blasts)
• AMV564 brings T-cells together with the CD33⁺ cell leading to:
  • T-cell activation, proliferation and differentiation as well as cytokine release
  • T-cell mediated cell death of the CD33⁺ cells

Study design and patient characteristics

• Trial name: AMV564-101
• Phase I trial in 33 adult patients with R/R high-risk AML (Patient characteristics: Table 1)
  • Prior induction regimens: 1–4
  • Patients who had relapsed post-allogeneic hematopoietic stem cell transplant (allo-HSCT) and patients with secondary AML were allowed
  • Normal renal/hepatic function was required
• AMV564 was administered as a 14-day continuous infusion
• Dose-escalation (0.5mcg–450mcg) in a 3+3 design:
  • Enrolled: doses up to 250mcg currently in 33 patients
  • Enrolling: 300mcg cohort
  • To be enrolled: 450mcg cohort
• Objectives:
  • Define maximum tolerated dose (MTD) and recommended phase II dose (RP2D)
  • Evaluate efficacy, assess pharmacokinetics and assess biomarkers

Table 1: Patient characteristics for AMV564-101 trial

Characteristic

 

Total (N)

33

Median age (years)

71.5 (24–85)

ECOG score ≥2

12%

Secondary AML

73%

Prior allo-HSCT

9%

Prior intensive chemotherapy

64%

MRC cytogenetic risk – unfavorable

58%

Enrollment bone marrow (BM) blasts

30% (3%–96%)

Baseline white blood cell count (x10⁹/L)

2.1 (0.2–13.8)

MTD and dose limited toxicities (DLTs) 

• No DLTs and no grade 3 or 4 events of cytokine release syndrome (CRS) were observed up to 250mcg
• The most common treatment-emergent adverse events (TEAEs) occurring in ≥30% of patients were; peripheral edema, pyrexia, nausea, headache, CRS, cough, constipation, febrile neutropenia and diarrhea
• The most common related TEAEs occurring in ≥20% of patients were CRS and pyrexia
• The treatment was well-tolerated overall and no steroids were required

Response rate

• Best response in the bone marrow:
  • One complete remission (CR), one CR with incomplete blood count recovery (CRi) and one partial remission (PR) were observed in 9 evaluable patients receiving more than 2 cycles of AMV564 (Table 2)
  • A reduction in spleen size was seen in one patient
  • Best responses in patients receiving more than 2 cycles of AMV564 are shown in Table 2
• Since AML is a rapidly progressing disease, achieving stable disease (SD) on this regimen is meaningful
• In relation to duration of response, two patients responded for up to seven months; one of whom had achieved a CRi and one who had SD
• A selective depletion of leukemic blasts in the BM and MDSCs was also observed in 17 of 27 patients supporting the hypothesized immune mediated mechanism of action of the drug

Table 2: Response of patients receiving more than 2 cycles of AMV564

Target dose level (mcg)

Number of cycles

Best response (throughout cycles)

Response at last assessment  

100

5

SD

SD

100

2

PR

PR

150

6

CRi

SD

150

2

SD

SD

200

2

CR

SD

200

2

SD

SD

250

2

SD

SD

Continued dose escalation

A new lead-in dose regimen, without steroids, is being used to allow for continued dose escalation as shown in Table 3.

Table 3: Lead-in dosing schedule

Lead-in dose (mcg)*

Target dose (mcg)

Cycles

Grade 1

Grade 2

Not applicable

15

30

3

1

15

100

21

4

0

15–100

150

4

2

0

15–100

200

3

0

2

15–100

250

1

0

1

15–30–100–150–200

250

3

0

1

*In patients who received 15mcg and then 100 mcg, they received 15mcg for 3 days followed by 100mcg for 3 days. In the last patient in the table, 15mcg, 30mcg, 100mcg, 150mcg and 200mcg were given for 1 day at a time.

Conclusion

Prof. Roboz, and fellow authors on the study, concluded that AMV564 was well-tolerated up to doses of 250mcg, with no DLTs observed to date. There were only limited grade 1 and 2 CRS events, and a lead-in dose schedule is now being utilized to continue the escalation up to 450mcg. Some responses and stabilization of the disease for up to 7 months were observed.